Denna webbsida är endast avsedd för läkare och sjukvårdspersonal med förskrivningsrätt.

Positivt CHMP-utlåtande för Imbruvica (ibrutinib)

Positivt CHMP-utlåtande för Imbruvica (ibrutinib): utökad indikation för kombinationsbehandling under fast behandlingstid för vuxna patienter med tidigare obehandlad kronisk lymfatisk leukemi

 

Hela pressreleasen

Nytt angreppssätt vid dödlig njurcancer

I en studie vid Karolinska Institutet har forskare kopplat motståndskraft mot behandling vid en dödlig form av njurcancer till låga nivåer av cellernas energiproducenter, mitokondrierna. När forskarna med hjälp av läkemedel ökade mängden mitokondrier blev cancercellerna sårbara för behandlingen. Fynden har publicerats i Nature Metabolism och ger hopp om bättre riktade cancerläkemedel.

För att mitokondrier ska kunna tillverka energi behöver de syre och de är den komponent i cellen som kräver allra mest syre. Men hur mitokondrier fungerar i celler med syrebrist och är kopplat till motståndskraft vid cancerbehandling har varit oklart.

Susanne Schlisio. Foto: Flynn Larsen.

Vi har för första gången kunnat visa hur nybildningen av mitokondrier styrs vid syrebrist och hur denna process förändras i cancerceller med VHL-mutationer, säger Susanne Schlisio, senior forskare och gruppledare vid institutionen för mikrobiologi, tumör- och cellbiologi, Karolinska Institutet, som har lett studien.

Att vanliga celler omvandlas till cancerceller förhindras av en gen kallad von Hippel-Lindau, VHL. År 2019 gick Nobelpriset i fysiologi eller medicin till upptäckten att VHL var en del av cellernas syreavkänningssystem. Normalt ska VHL bryta ned ett annat protein kallat HIF. När VHL är muterat kan inte HIF brytas ned och då lider patienten av en sjukdom kallad VHL-syndrom. Cellerna reagerar då som om de har syrebrist, trots att det finns syre. VHL-syndrom ger kraftigt förhöjd risk att utveckla både god- och elakartade tumörer. Njurcancer med VHL-syndrom har dålig prognos med en femårsöverlevnad på knappt 12 procent.

I den aktuella studien undersökte forskarna proteininnehållet i cancerceller från patienter med olika varianter av VHL-syndrom och hur det skilde sig från en grupp personer med en speciell mutation i VHL kallad Chuvash. Mutationen är involverad i olika syrebrist-relaterade tillstånd utan tumörutveckling. De med mutationen hade normal mängd mitokondrier i sina celler, medan de med VHL-syndrom hade få.

Cellerna blev mottagliga för läkemedel

För att öka mängden mitokondrier i njurcancerceller med VHL-syndrom tillförde forskarna en så kallad mitokondrieproteas-hämmare. Genom att hämma ett proteas kallat LONP1 ökade mängden mitokondrier i njurcancerceller. Cellerna blev då mottagliga för cancerläkemedlet sorafenib som de tidigare stått emot. I musstudier ledde kombinationsbehandlingen till minskad tumörtillväxt.

Vi hoppas att den nya kunskapen ska göra det möjligt att ta fram mer specifika LONP1 proteas-hämmare för att behandla VHL-kopplad klarcellig njurcancer. Vårt fynd kan kopplas till all slags cancer vid VHL-syndrom, exempelvis de neuroendokrina tumörformerna feokromocytom och paragangliom, inte bara njurcancer, säger Shuijie Li, postdoktor i Schlisios forskargrupp och studiens försteförfattare.

Studien har fått stöd från Barncancerfonden, Cancerfonden, Vetenskapsrådet, Knut och Alice Wallenbergs Stiftelse, ERC Synergy grant (projekt ”Döda eller differentiera”) samt Paradifference Foundation.

Publikation

Impaired oxygen-sensitive regulation of mitochondrial biogenesis within the von Hippel-Lindau syndrome.” Shuijie Li, Wenyu Li, Juan Yuan, Petra Bullova, Jieyu Wu, Xuepei Zhang, Yong Liu, Monika Plescher, Javier Rodriguez, Oscar C. Bedoya-Reina, Paulo R. Jannig, Paula Valente-Silva, Meng Yu, Marie Arsenian Henriksson, Roman A. Zubarev, Anna Smed-Sörensen, Carolyn K. Suzuki, Jorge L. Ruas, Johan Holmberg, Catharina Larsson, C. Christofer Juhlin, Alex von Kriegsheimand Yihai Cao, Susanne Schlisio, Nature Metabolism, online 27 juni 2022, doi: 10.1038/s42255-022-00593-x.

Novartis får positiv rekommendation för godkännande av CHMP för Scemblix®

Novartis får positiv rekommendation för godkännande av CHMP för Scemblix® , en ny behandling för vuxna patienter med KML.

  • With unique STAMP mechanism of action, Scemblix could provide a new option for patients in Europe with chronic myeloid leukemia (CML) who have suffered intolerance or inadequate response with at least two prior tyrosine kinase inhibitor treatments1
  • Positive opinion based on data from pivotal Phase III ASCEMBL trial, showing a near doubling in major molecular response rate for patients treated with Scemblix® (asciminib) vs. Bosulif®* (bosutinib) (25.5% vs. 13.2%) and more than three times lower discontinuation rate due to adverse reactions (5.8% vs 21.1%) at 24 weeks1
  • CHMP recommendation comes after the approval of Scemblix by the US FDA and other countries’ regulatory authorities, potentially broadening access for more patients to Novartis transformative therapies in CML

Novartis today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion and recommended granting marketing authorization for Scemblix® (asciminib) for the treatment of adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP), previously treated with two or more tyrosine kinase inhibitors (TKIs). If approved, Scemblix will be the first CML treatment in Europe that works by specifically targeting the ABL myristoyl pocket (also known as a STAMP inhibitor in scientific literature), representing an important therapeutic advancement for patients who experience intolerance and/or resistance to currently available TKI therapies1.

 

It is estimated that, every year, more than 6,300 people will be diagnosed with CML in Europe2. While many patients will benefit from available TKI therapies, a significant proportion may experience intolerance or resistance to these treatments3-10. In an analysis of patients with CML treated with two prior TKIs, approximately 55% reported intolerance to previous treatment; and a pooled analysis of patients in the second-line setting revealed that up to 70% are unable to achieve major molecular response (MMR) within two years of follow-up11-14.

 

”Although CML treatments have advanced over the last 20 years, many patients continue to experience side effects and resistance to treatment, affecting their quality of life and putting them at risk of disease progression or even death,” says Dr. Andreas Hochhaus, Head of the Department of Hematology and Medical Oncology at Jena University Hospital in Germany. ”If approved, the novel mechanism of action of Scemblix brings us another option to combat these challenges faced by patients — offering new hope in the management of their disease.”

 

The positive CHMP opinion for Scemblix is based on results from the pivotal Phase III ASCEMBL trial, which showed a near doubling of MMR rate for patients treated with Scemblix vs. Bosulif®* (bosutinib) (25.5% vs. 13.2%) at 24-weeks, with a more than three times lower discontinuation rate due to adverse reactions (5.8% vs. 21.1%)1. The most common (incidence ≥ 20%) adverse reactions reported in this analysis were thrombocytopenia (29.5%) and neutropenia (23.1%) in the Scemblix arm; and diarrhea (71.1%), nausea (46.1%), increased ALT (28.9%), vomiting (26.3%), rash (23.7%), increased AST (21.1%) and neutropenia (21.1%) in the Bosulif arm1.

 

These results were confirmed in longer-term follow-up, where the MMR rate at week 96 was more than double with Scemblix (37.6%, 95% CI: 29.99-45.65) compared with Bosulif (15.8%, 95% CI: 8.43-25.96). This data was shared at oral presentations during the American Society for Clinical Oncology (ASCO) and the European Hematology Association (EHA) annual meetings in June 202215,16.

 

“We are pleased with the recommendation of Scemblix and hope to offer patients living with CML in Europe timely access to this innovative therapy, if approved,” said Haseeb Ahmad, President, Europe, Novartis. “We’ve worked relentlessly to improve CML care over the past two decades, and must seize this opportunity to help patients in need achieve better outcomes. With the strong clinical results seen to-date, we believe we have the potential to transform the standard of care in CML yet again with Scemblix.”

 

The CHMP recommended approval of Scemblix in CML will be referred to the European Commission (EC). The EC will review the CHMP recommendations and deliver a final decision in the coming months.

 

About Scemblix® (asciminib)

Scemblix is the first CML treatment that acts as a STAMP inhibitor, specifically targeting the ABL myristoyl pocket1. This novel mechanism of action may help address resistance in patients with CML previously treated with two or more TKIs and overcome mutations at the defective BCR::ABL1 gene, which is associated with the over-production of leukemic cells1,17-23.

 

Scemblix represents an important development for patients who experience resistance and/or intolerance to currently available TKI therapies, and it is being studied across multiple treatment lines for CML-CP, both as a monotherapy and in combination1,17-31. Specifically, the ASC4FIRST Phase III study (NCT04971226) evaluates Scemblix in newly diagnosed adult patients with Ph+ CML-CP vs. an investigator-selected TKI, with recruitment proceeding ahead of plan25.

 

Novartis has initiated regulatory filings for Scemblix in multiple countries and regions across the globe. In October 2021, the US FDA granted accelerated approval of Scemblix for adult patients with Ph+ CML-CP, previously treated with two or more TKIs based on MMR rate at 24 weeks, and full approval for adult patients with Ph+ CML-CP with the T315I mutation. In accordance with the Accelerated Approval Program, continued approval for the first indication may be contingent upon verification and description of clinical benefit from confirmatory evidence. Further data has been shared with the FDA for evaluation 32. Scemblix has received approval in several countries outside the US for adult patients with Ph+ CML-CP with resistance or intolerance to at least two or more previous therapies.

 

About Novartis Commitment to CML

Novartis has a long-standing scientific commitment to patients living with CML. For more than 20 years, our bold science has helped transform CML into a chronic disease for many patients. Despite these advancements, we’re not standing still. We continue to research ways to target the disease, seeking to address the challenges with treatment resistance and/or intolerance that many patients face. Novartis also continues to reimagine CML care through its commitment to sustainable access for patients and collaboration with the global CML community.

 

Disclaimer

This press release contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” “seek,” “look forward,” “believe,” “committed,” “investigational,” “pipeline,” “launch,” or similar terms, or by express or implied discussions regarding potential marketing approvals, new indications or labeling for the investigational or approved products described in this press release, or regarding potential future revenues from such products. You should not place undue reliance on these statements. Such forward-looking statements are based on our current beliefs and expectations regarding future events, and are subject to significant known and unknown risks and uncertainties. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those set forth in the forward-looking statements. There can be no guarantee that the investigational or approved products described in this press release will be submitted or approved for sale or for any additional indications or labeling in any market, or at any particular time. Nor can there be any guarantee that such products will be commercially successful in the future. In particular, our expectations regarding such products could be affected by, among other things, the uncertainties inherent in research and development, including clinical trial results and additional analysis of existing clinical data; regulatory actions or delays or government regulation generally; global trends toward health care cost containment, including government, payor and general public pricing and reimbursement pressures and requirements for increased pricing transparency; our ability to obtain or maintain proprietary intellectual property protection; the particular prescribing preferences of physicians and patients; general political, economic and business conditions, including the effects of and efforts to mitigate pandemic diseases such as COVID-19; safety, quality, data integrity or manufacturing issues; potential or actual data security and data privacy breaches, or disruptions of our information technology systems, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

 

References

  1. Rea D, et al. A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After≥ 2 Prior TKIs. Blood. 2021. DOI: 10.1182/blood.2020009984. PMID: 34407542.
  2. Hoffmann, V., Baccarani, M., Hasford, J. et al. The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries. Leukemia 29, 1336–1343 (2015). https://doi.org/10.1038/leu.2015.73
  3. Flis S, et al. Chronic myelogenous leukemia, a still unsolved problem: pitfalls and new therapeutic possibilities. Drug Des Devel Ther. 2019;13:825-843.
  4. Akard LP, et al. The “Hit Hard and Hit Early” Approach to the Treatment of Chronic Myeloid Leukemia: Implications of the Updated National Comprehensive Cancer Network Clinical Practice Guidelines for Routine Practice. Clin Adv Hematol Oncol. 2013;11(7):421-432.
  5. Cortes JE, et al. Long-term bosutinib for chronic phase chronic myeloid leukemia after failure of imatinib plus dasatinib and/or nilotinib. Am J Hematol. 2016;91(12):1206-1214.
  6. Cortes JE, et al. Ponatinib efficacy and safety in Philadelphia chromosome–positive leukemia: Final 5-year results of the phase 2 PACE trial. Blood. 2018;132(4):393-404.
  7. Garg RJ, et al. The use of nilotinib or dasatinib after failure to 2 prior tyrosine kinase inhibitors: long-term follow-up. Blood. 2009;114(20):4361-4368
  8. Hochhaus A, et al. European LeukemiaNet 2020 recommendations for treating chronic myeloid leukemia. Leukemia. 2020;34:966-984
  9. Cortes JE., et al. Final 5-Year Study Results of DASISION: The Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients Trial. J Clin Oncol. 2016;34:2333-2340.
  10. Steegmann JL., et al. European LeukemiaNet recommendations for the management and avoidance of adverse events of treatment in chronic myeloid leukaemia. Leukemia. 2016;30:1648-1671.
  11. Giles FJ, et al. Nilotinib is active in chronic and accelerated phase chronic myeloid leukemia following failure of imatinib and dasatinib therapy. Leukemia. 2010; 24(7):1299–1301.
  12. Kantarjian HM, et al. Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results. Blood. 2010;117(4):1141-1145. doi:10.1182/blood-2010-03-277152.
  13. Shah NP, et al. Potent, transient inhibition of BCR-ABL with dasatinib 100 mg daily achieves rapid and durable cytogenetic responses and high transformation-free survival rates in chronic phase chronic myeloid leukemia patients with resistance, suboptimal response or intolerance to imatinib. Haematologica. 2010 Feb;95(2):232-40. doi: 10.3324/haematol.2009.011452. PMID: 20139391; PMCID: PMC2817025.
  14. Gambacorti-Passerini C, et al. Bosutinib efficacy and safety in chronic phase chronic myeloid leukemia after imatinib resistance or intolerance: Minimum 24-month follow-up. Am J Hematol. 2014 Jul;89(7):732-42. doi: 10.1002/ajh.23728. Epub 2014 Apr 28. PMID: 24711212; PMCID: PMC4173127.
  15. Cortes JE, et al. Oral presentation at ASCO 2022; June 3-7, 2022. Chicago IL and virtual. Abstract 7004
  16. Réa D, et al. Oral presentation at EHA 2022; June 9-17, 2022. Vienna Austria and virtual. Abstract S155
  17. Wylie AA, et al. The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1. Nature. 2017;543(7647):733-737.
  18. Schoepfer J, et al. Discovery of Asciminib (ABL001), an Allosteric Inhibitor of the Tyrosine Kinase Activity of BCR-ABL1. J Med Chem. 2018;61(18):8120-8135.
  19. Hughes TP, et al. Asciminib in Chronic Myeloid Leukemia after ABL Kinase Inhibitor Failure. N Engl J Med. 2019; 381(24):2315-2326.
  20. Hughes TP, et al. Expanded Phase 1 Study of ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Reveals Significant and Durable Responses in Patients with CML-Chronic Phase with Failure of Prior TKI Therapy. Poster presented at: ASH Annual Meeting & Exposition; Dec. 5, 2016.
  21. Ottmann OG, et al. ABL001, a Potent, Allosteric Inhibitor of BCR-ABL, Exhibits Safety and Promising Single- Agent Activity in a Phase I Study of Patients with CML with Failure of Prior TKI Therapy. Blood. 2015;126(23):138.
  22. Mauro MJ, et al. Combination of Asciminib Plus Nilotinib (NIL) or Dasatinib (DAS) in Patients (PTS) with Chronic Myeloid Leukemia (CML): Results from a Phase 1 Study. Poster presented at: EHA Annual Meeting; June 15, 2019.
  23. Cortes JE, et al. Combination Therapy Using Asciminib Plus Imatinib (IMA) in Patients (PTS) with Chronic Myeloid Leukemia (CML): Results from a Phase 1 Study. Poster presented at: EHA Annual Meeting; June 15, 2019.
  24. ClinicalTrials.gov. 2017. Study of Efficacy of CML-CP Patients Treated with ABL001 Versus Bosutinib, Previously Treated With 2 or More TKIs. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT03106779.
  25. ClinicalTrials.gov. 2021. A Study of Oral Asciminib Versus Other TKIs in Adult Patients With Newly Diagnosed Ph+ CML-CP. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04971226.
  26. ClinicalTrials.gov. 2020. Asciminib in Monotherapy for Chronic Myeloid Leukemia in Chronic Phase (CML-CP) With and WithoutT315I Mutation (AIM4CML). [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04666259.
  27. ClinicalTrials.gov. 2018. Study of Efficacy And Safety Of Asciminib In Combination With Imatinib In Patients With Chronic Myeloid Leukemia In Chronic Phase (CML-CP). [online] Available at: https://clinicaltrials.gov/ct2/show/NCT03578367.
  28. ClinicalTrials.gov. 2021. Study of Efficacy and Safety of CML-CP Patients Treated With Asciminib Versus Best Available Therapy, Previously Treated With 2 or More Tyrosine Kinase Inhibitors. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04795427.
  29. ClinicalTrials.gov. 2014. A Phase I Study of Oral ABL001 in Patients With CML or Ph+ ALL. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT02081378.
  30. ClinicalTrials.gov. 2021 Asciminib Treatment Optimization in ≥ 3rd Line CML-CP. [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04948333
  31. ClinicalTrials.gov. 2021. Study to Determine the Dose and Safety of Asciminib in Pediatric Patients With Chronic Myeloid Leukemia [online] Available at: https://clinicaltrials.gov/ct2/show/NCT04925479
  32. Scemblix [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2021.

AbbVie presenterar nya resultat från fas II-studie med epcoritamab (DuoBody®-CD3xCD20) hos patienter med relapserat/refraktärt storcelligt B-cellslymfom

AbbVie meddelar de första resultaten för patienter med storcelligt B-cellslymfom (LBCL) i den kliniska fas II-studien, EPCORE™ NHL-1, som utvärderar epcoritamab (DuoBody®-CD3xCD20), en subkutan bispecifik antikropp. Patienter som tidigare hade fått minst två linjer av anti-lymfomterapi inklusive chimär antigenreceptor (CAR) T-cellsterapi erhöll ett varaktigt behandlingssvar med epcoritamab. Dessa late-breaking resultat presenterades muntligen som en del av presidentsymposiet vid den årliga hematologikongressen, EHA (European Hematology Association Congress).

  • Epcoritamab visar kliniskt meningsfull effekt hos patienter med svårbehandlat refraktärt storcelligt B-cellslymfom (LBCL)
  • Patientpopulationen uppnådde en total svarsfrekvens (ORR – Overall Response Rate) på 63 procent och komplett respons (CR – Complete Response) på 39 procent; CAR T-naiva patienter uppnådde 69 procent ORR och 42 procent CR; patienter som tidigare behandlats med CAR T uppnådde 54 procent ORR och 34 procent CR
  • Säkerhetsprofilen överensstämmer med vad som tidigare observerats
  • Resultaten valdes ut och rapporterades som en del av en late-breaking muntlig presentation på Presidential Symposium vid den årliga hematologikongressen, EHA

Här hittar du hela pressreleasen på engelska

Paradigmskifte i njurcancervården – Snabb utveckling av nya behandlingsmöjligheter

Paradigmskifte, golden age, rekordsnabb utveckling av nya behandlingar. Det finns många sätt att beskriva det som händer inom njurcancerområdet just nu. Från att länge ha varit en svårbehandlad cancerform finns det idag en rad god kända behandlingar som förlänger överlevnaden. Och för första gången kan numera även njurcancerpatienter få adjuvant behandling. Västra Götalandsregionen är tidigt ute när det gäller implementeringen av de nya behandlingsmetoderna.
– Ja, det är nu det händer och jag är glad över att få vara med under den här tiden, säger onkologen Emma Mangelus, som arbetar i njure/melanom-teamet på Sahlgrenska Universitetssjukhuset.

Under de senaste åren har det skett en närmast explosionsartad utveckling inom njurcancervården, främst inom området immunterapier där ett stort antal nya indikationer inom gruppen PD-1- och PD-L1- hämmare nyligen har godkänts. Tack vare nya läkemedel och nya kombinationsbehandlingar finns det nu goda möjligheter att erbjuda även njurcancerpatienter effektiv behandling.

– Eftersom njurcancer inte är känslig för strålning eller cytostatika innebär de nya terapierna ett stort genombrott inom detta område. Vi har arbetat med så kallad dubbel immunterapi som första linjens behandling vid intermediär och högrisk klarcellig njurcancer, den vanligaste formen av njurcancer, sedan 2018 och under det senaste halvåret har vi även använt oss av några av de nyligen godkända kombinationsbehandlingarna, det vill säga TKI och checkpointhämmare.

FRAMGÅNGSRIKT ARBETE I TEAM
Det finns flera förklaringar till att man ligger långt framme med dessa nya behandlingar i Göteborg. En är att man här arbetar med njurcancer och malignt melanom i ett team.
– Malignt melanom var en av de första cancersjukdomarna som behandlades med immunterapi, så vårt team har stor erfarenhet av att arbeta med dessa läkemedel som har visat sig vara effektiva också vid njurcancer. Vi lär oss av varandra, förklarar hon. Den andra förklaringen är att Västra Götalandsregionen har ett system för introduktionsfinansiering för nya läkemedel, så kallat ordnat införande, för att pröva dessa nya läkemedel under två år.

– Vi har tillgång till alla nya godkända kombinationsbehandlingar, både TKI-preparat som kan ge en snabb effekt och immunterapi där effekten dröjer men kan bli långvarig. Vid vissa aggressiva former gäller det att agera snabbt, och just kombinationen av TKI och immunterapi kan ge en både snabb OCH långverkande effekt. Studier visar att cirka tio procent av patienterna uppnår komplett remission, det vill säga att all mätbar sjukdom försvinner, och att överlevnaden ökar jämfört med enbart behandling med TKI-preparat.

Läs hela artikeln